HIV protease inhibitors in combination with reverse transcriptase inhibitors continue to be first line antiviral agents for control of HIV infection. While protease inhibitors are most useful in the treatment of AIDS, there are serious limitations including major toxicity, complexity, and perhaps the most serious of all, the emergence of mutidrug resistant strains of HIV. There is now ample evidence that these strains can be transmitted. In addition, tolerance and adherence to complex medical regimens are becoming a critical issue. The drugs must be taken in gram quantities daily because of low oral bioavailability. Most currently approved protease inhibitors (PIs) are associated with complex side effects including peripheral lipodystrophy, hyperlipidemia and insulin resistance. In this context, our current research emphasis has been to design and synthesize nonpeptidyl protease inhibitors and optimize their potency against mutant strains resistant to the currently approved protease inhibitors. We recently developed a number of novel nonpeptidyl HIV protease inhibitors based upon X-ray structures of the protein-ligand complexes. One of these inhibitors is currently undergoing clinical trials at Tibotec -Virco in Belgium. Based upon X-ray structures of our inhibitors, we have generated a number of interesting small molecule leads. This work now forms the basis of our proposed studies in which the power of crystallography and molecular modeling will be utilized to further develop a new generation of nonpepfidyl protease inhibitors with improved pharmacological and resistance profiles. Our specific aims of the present proposal are: (a) to perform structure-activity studies of lead small molecule inhibitors; (b) to further optimize the potent inhibitors' resistance profiles based upon crystallographic information; (c) to design and synthesize novel nonpeptidyl inhibitors incorporating novel designed ligands and templates; (d) to incorporate functionalities for combating drug resistance and improving oral absorption poperties; (e) to conduct in-depth resistance profile s to further optimize inhibitors. Our proposed research effort will involve the realms of organic synthesis, medicinal chemistry, biochemistry, molecular biology, protein ligand X-ray crystallography and molecular modeling. Besides the broad range of scope and generality, this line of research will provide excellent opportunities to teach and train students in the laboratory.